Gamma-hydroxybutyrate for treating symptoms associated with alcohol withdrawal and preventing relapses for people who are dependent on alcohol

Excessive long term alcohol consumption can lead to dependence on alcohol. This means that when a person stops drinking suddenly he or she experiences withdrawal symptoms. The main goals for clinical management of alcohol withdrawal are to minimize the severity of symptoms and facilitate entry into a treatment program, so that the person can achieve and maintain abstinence from alcohol. Symptoms of withdrawal range from tremor, nausea, anxiety, restlessness and insomnia to more severe effects such as seizures, hallucinations, agitation and delirium. Progression to coma and cardiac arrest is possible. Medications that are intended to help people who are dependent on alcohol to withdraw from it include benzodiazepines, anticonvulsants and gamma-hydroxybutyrate (GHB). GHB was first available as a health food and body-building supplement, but reports of adverse events led to its withdrawal for that purpose.

Thirteen randomised controlled trials involving 648 participants were included in this review. Eleven of these were conducted in Italy. However, there is not enough reliable evidence from the research that has been done to date to be confident of a difference between GHB and placebo, or to determine reliably if GHB is more or less effective than other drugs for the treatment of alcohol withdrawl or the prevention of relapses.

Six trials with a total of 286 participants evaluated the effectiveness of GHB in reducing withdrawal syndrome. These compared the drug with a variety of other interventions, making it impossible to use them all in a single analysis. One study suggests that GHB might reduce withdrawal symptoms more than a placebo, but this is based on a very small number of patients. No strong differences were observed between GHB and benzodiazepines or Clomethiazole. In the other comparisons, the differences were not statistically significant.

Seven trials involving 362 participants tested the use of GHB to treat alcohol dependence or prevent relapses if a person was already detoxified (mid-term outcomes). These included several different comparisons, so each analysis was able to include only one or two trials; and the trials were generally small (range 17 to 98 participants). GHB did appear to be better than Naltrexone and Disulfiram in maintaining abstinence and preventing craving, based on two trials and one trial respectively for these comparisons. The most consistently reported side effect of GHB was dizziness and vertigo, with this being more common at higher doses. The findings of this review should be considered alongside concerns that have been raised about GHB regarding the risk of developing addiction, and the misuse or abuse of the drug, suggesting to use GHB only under strict medical surveillance.

Authors' conclusions: 

There is insufficient randomised evidence to be confident of a difference between GHB and placebo, or to determine reliably if GHB is more or less effective than other drugs for the treatment of alcohol withdrawl or the prevention of relapses. The small amount of randomised evidence available suggests that GHB 50mg may be more effective than placebo in the treatment of AWS, and in preventing relapses and craving in previously detoxified alcoholics during the first 3 months of follow-up. This review does not provide evidence in favour or against GHB compared to benzodiazepines and Clomethiazole for treatment of AWS; but, again based on a small amount of randomised evidence, GHB appears better than NTX and Disulfiram in maintaining abstinence and preventing craving in the medium term (3 to 12 months). The review does not provide evidence of a difference in side effects between GHB and benzodiazepines, NTX or Disulfiram. These findings should be considered alongside concerns that have been raised about GHB regarding the risk of developing addiction, and the misuse or abuse of the drug, suggesting to use GHB only under strict medical surveillance.

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Background: 

Chronic excessive alcohol consumption may lead to dependence, and to alcohol withdrawal syndrome (AWS) in case of abrupt drinking cessation. Gamma-hydroxybutyric acid (GHB) can prevent and suppress withdrawal symptoms, and improve the medium-term abstinence rate. However, clear estimates of its beneficial and harmful effects have not been yet established.

Objectives: 

To evaluate the efficacy and safety of GHB for the treatment of AWS and the prevention of relapse.

Search strategy: 

We searched the Cochrane Drugs and Alcohol Group's Register of Trials (October 2008), PubMed, EMBASE, CINAHL (January 2005 to October 2008), EconLIT (1969 to February 2008), and reference lists of retrieved articles.

Selection criteria: 

Randomized controlled trials (RCT) and Controlled Prospective Studies (CPS) evaluating the efficacy and the safety of GHB versus placebo or other pharmacological treatments.

Data collection and analysis: 

Three authors independently extracted data and assessed the methodological quality of the studies.

Main results: 

Thirteen RCTs were included, 11 of which had been conducted in Italy.

For alcohol withdrawal syndrome, comparing GHB 50mg versus placebo, results from 1 study (23 participants) favour GHB for withdrawal symptoms: MD -12.1 (95% CI -15.9 to -8.29), but tolerated side effects were more frequent in the GHB group: RR 16.2 (95% CI 1.04 to 254.9; based on 7 of 11 patients in the GHB group developing transitory vertigo compared to none in the placebo group). In the comparison of GHB 50mg versus Clomethiazole, results from 1 study (21 participants) favour GHB for withdrawal symptoms: MD -3.40 (95% CI -5.09 to -1.71). For GHB 100mg versus Clomethiazole, results from 1 study (98 participants) favour Clomethiazole for side effects: RR 1.84 (95% CI 1.19 to 2.85).

At mid-term, comparing GHB 50mg/day with placebo, 1 study (71 participants, 3 months follow-up) favour GHB for abstinence rate (RR 5.35, 95% CI 1.28 to 22.4), controlled drinking (RR 2.13, 95% CI 1.07 to 5.54), relapses (RR 0.36, 95% CI 0.21 to 0.63), and number of daily drinks (MD -4.60, 95% CI -6.18 to -3.02). On abstinence, GHB performed better than Naltrexone (NTX) (2 studies, 64 participants) (RR 2.59, 95% CI 1.35 to 4.98 at 3 months) and than Disulfiram (1 study, 59 participants) (RR 1.66, 95% CI 0.99 to 2.80 at 12 months, slightly significant). The combination of GHB and NTX was better than NTX for abstinence (RR 12.3, 95% CI 1.79 to 83.9 at 3 months; 1 study, 35 participants). The combination of NTX, GHB and Escitalopram was better than Escitalopram alone for abstinence (RR 2.02 95% CI 1.03 to 3.94 at 3 months; RR 4.58, 95% CI 1.28 to 16.5 at 6 months; 1 study, 23 participants). For Alcohol Craving Scale, results favour GHB over placebo (MD -4.50, 95% CI -5.81 to -3.19 at 3 months; 1 study, 71 participants) and over Disulfiram at 12 months (MD -1.40, 95% CI -1.86 to -0.94, from 1 study with 41 participants).

All other comparisons and outcomes did not show significant differences.

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